Helper and cytotoxic T cell responses specific for myelin basic protein

Multiple Sclerosis (MS) is a complex, neurological disorder whose etiology is unknown. MS is believed to be autoimmune in origin for several reasons. First, extensive immunopathology is observed in the CNS of MS patients, MS plaques contain CD4+ and CD8+ T cells. Second, MS susceptibility is linked to MHC class II immune response genes. Third, an animal model that exhibits many similarities to MS, Experimental autoimmune encephalomyelitis (EAE), is induced by specific activation of the immune system via immunization with CNS antigens. These observations suggest that MS arises when self-reactive T cells specific for myelin antigens are erroneously activated, cross the blood brain barrier and attack myelin forming cells.; Here we investigate how individual epitopes of MBP have a differing ability to be recognized by the immune system. The MBP 121-140 epitope induces strong T cell tolerance while the MBP Ac1-11 epitope appears to be ignored by the immune system. Using a TCR Tg approach, it is found that MBP 121-140-specific T cells recognize MBP within the thymus, spleen and lymph nodes of wild-type mice. MBP 121-140-specific thymocytes undergo massive clonal deletion upon the presentation of MBP by Bone Marrow-derived antigen presenting cells in the thymus. The ability and efficiency of distinct MBP epitopes to induce T cell tolerance correlates with the ability of T cells to recognize low concentrations of ligand, likely a product of the stability of the MBP-peptide/MHC complex.; The ability to induce T cell mediated autoimmunity in animal models clearly demonstrates that T cell tolerance is incomplete. Studies of EAE have shown that activation of myelin-specific CD4+ T cells in vivo are sufficient to generate CNS autoimmunity. Although MS plaques contain CD8+ T cells, the ability of cytotoxic T cell specific for CNS antigens to induce CNS autoimmunity had yet to be determined. Here, we demonstrate that myelin specific CD8+ T cells can induce CNS autoimmunity with multiple characteristics of MS distinct from CD4 + T cell mediated EAE.